PROJECT 3: This project will elucidate basic mechanisms linking sleep disordered breathing with accelerated decline in pulmonary and systemic manifestations of COPD. Its overall hypothesis is that sleep disordered breathing in COPD triggers pulmonary and systemic inflammatory responses, which can be mitigated by a novel therapeutic strategy. A combination of human and murine models will be utilized to address this hypothesis. Human studies are designed to elucidate unique physiologic mechanisms of sleep disordered breathing in COPD, characterize its impact on nocturnal oxygenation and systemic inflammation, and pilot novel therapy to prevent accelerated decline in COPD. These human studies will derive crucial support from parallel SCCOR studies of inflammatory profiles and therapeutic trials in COPD patients. In complementary murine studies, this project will model the effects of intermittent hypoxemia in sleep disordered breathing, and in concert with basic lung biologists involved in this SCCOR program, will dissect fundamental molecular antimorphogenic and proinflammatory mechanisms of COPD progression. Our proposal has immediate clinical implications for the patient with COPD. It will provide new non-invasive physiologic and serum markers of disease progression. These markers may be used to stratify COPD patients at increased risk of morbidity and mortality, target particular patient subgroups for early intervention, and monitor therapeutic responses. This project will provide fundamental molecular, physiologic and therapeutic insights from a unique combination of human and murine studies, which will ultimately improve health outcomes in COPD.